The medicinal substance known by the INN bicalutamide is also known as N-[4′-cyano-3′-trifluoromethyl-phenyl]-3-[4″-fluorophenylsulfonyl]-2-hydroxy-2-methyl-propionamide.
Racemic bicalutamide can be prepared by known processes, e.g. the ones described or referred to in U.S. Ser. No. 10/498,862 (corresponding to WO 03/097590 A1).
Bicalutamide and related acylanilides are compounds exhibiting antiandrogenic activity. A racemic bicalutamide containing drug for the treatment of prostate cancer is marketed under the trade name CASODEX® (Astra Zeneca).
Bicalutamide is sparingly soluble in water and aqueous buffers at various pH values. Furthermore, the speed of being dissolved appears to depend on the particle size of the drug. WO 2004/100944 A1 and U.S. Pat. No. 6,861,557 B2 therefore describe the use of micronized bicalutamide in pharmaceutical preparations in order to enhance the speed of dissolution and, hence, the bioavailability of the drug. Moreover, bicalutamide is reported to crystallize in two different polymorphic forms, called I and II, or to be amorphous (cf. WO 2004/100944 A1). In addition to particle size, the morphology, or changes of the morphology during storage, may affect the drug dissolution profile.
The principle of micronizing bicalutamide for said pharmaceutical preparations is the application of conventional micronization techniques (various types of mills, sieving procedures, etc.), as disclosed in Liebermann et. al., Pharmaceutical Dosage Forms: Tablets, Vol. 2, 2nd ed., Marcel Dekker, Inc. New York, 1990. However, due to the high toxicity of bicalutamide, all kinds of conventional micronization and sieving procedures require severe protective measures. Particularly potential dust development and cleaning procedures are of high risk. In addition, production of pharmaceutical dosage forms from micronized material is very costly since it involves granulation, drying, and sieving steps. Overall, the micronization and sieving steps, as well as the manufacturing of pharmaceuticals from micronized bicalutamide, may lead to significant losses of this expensive and toxic material.